GalNAc-functionalized metal–organic frameworks for targeted siRNA delivery: enhancing survivin silencing in hepatocellular carcinoma

Small interfering RNA (siRNA) is a potent method for silencing survivin mRNA within cells, offering a promising option for treating hepatocellular carcinoma (HCC) since survivin is specifically overexpressed in HCC cells. However, the clinical use of gene therapy with siRNA is limited by factors such as rapid enzyme degradation, low cell uptake, and non-specific distribution in the body. In this study, we investigate the use of a specially selected metal-organic framework (MOF) to encapsulate siRNA, with the aim of silencing survivin mRNA in HCC cells and reducing the survivin protein level. The MOF was functionalized with triantennary <i>N</i>-acetylgalactosamine (GalNAc), which has high affinity for asialoglycoprotein receptors that are overexpressed in HCC cells. Both <i>in vitro</i> and <i>in vivo</i> experiments showed that the GalNAc-decorated MOF specifically accumulated in HCC tumor tissue and was effectively endocytosed by HCC cells. The protective properties of the MOF increased the stability of siRNA and allowed for significant downregulation of survivin expression in HCC tumors, contributing to tumor inhibition through the suppression of cell proliferation and the induction of apoptosis. These findings highlight the potential of MOF-based siRNA delivery systems for targeted cancer therapy.